Patients with end-stage renal disease (ESRD) that require long-term hemodialysis need a reliable vascular access. The arteriovenous (A-V) fistula with its long patency rate and low complication profile is usually the first choice for vascular access creation. However, numerous fistulae fail due to neointimal hyperplasia (NIH). Despite the widely appreciated magnitude of this problem, there is paucity of research investigating the mechanisms responsible for neointimal formation in A-V fistulae. We have recently published two studies that describe the cellular dynamics of neointimal formation in the fistula wall. We have obtained evidences for the role of local progenitor cells during the pathological remodeling of A-V fistulae. In this proposal, we have brought together a multidisciplinary team of investigators to prove at the basic and clinical translational levels that the secretion of stem cel factor by smooth muscle cells in response to hemodynamic stress induces the myofibroblastic differentiation of vascular progenitors to initiate neointimal formation. We will also prove that inhibition of SCF/c-Kit signaling is sufficient to decrease and probably prevent neointimal formation in the fistula wall. We will test our hypothesis in four specific aims and six independen experiments that will demonstrate: 1) the contribution of local progenitor cells (c-Kit+) to the development of neointima in A-V fistulae~ 2) that inhibition of c-Kit ameliorate NIH in a porcine model of fistula stenosis, and 3) the relationship between c-Kit+ cells and the patency of human A-V fistulae. We will blend advanced transgenic mouse models with fine microsurgical techniques to successfully achieve our goals in the first two aims of the proposal. We will quantify the number of vascular wall progenitor cells (c-Kit+ Sox2+) in vein tissues collected at two different time points during two-stage brachiobasilic fistula creation in a cohort of 200 ESRD patients. We will correlate the number of progenitor cells in the fistula wall with the 8-wks blood flow rate and primary unassisted patency. In conclusion, with the successful accomplishment of this proposal, we are paving the way for the design of new therapeutic strategies that may prevent A-V fistula failure and reduce vascular access complications.